Ever since Maimonides advocated hand washing in the 11th century, surgeons have been seeking better ways of cleaning skin. In the 16th century, the postulate that germs (seminaria) provoked infection was set forth by Fracastoro. Historically, hand-washing for antiseptic purposes had its beginning about 150 years ago by a Hungarian physician, Ignaz Semmelweiss. He is credited with discovering how antiseptic technology can reduce patient mortality from hand-borne infectious agents. Most of the medical community in the 1800's was resistant to theories of antisepsis. In the post-Semmelweiss period, efforts to cleanse skin appear to have been concentrated on the skin of the physician or surgeon. It was not until after Lister and into the twentieth century that serious consideration was given as well to preparation of the patient's skin about to be breached by scalpel. For a review of antiseptics applied to the skin in the twentieth century, see Laufman, H., "Current use of skin and wound cleansers and antiseptics," The Am J Surgery, 157:359 (1989).
Antisepsis is the application of microbiocidal antimicrobial chemicals to skin in order to reduce the risk of infection. The microbial flora of the skin can be subdivided into two general groups: (1) transient and (2) resident organisms. An antiseptic is intended to kill both the transient and resident flora of the skin. One hopes to reduce each of these categories of organisms to the maximum extent possible. Transient flora are organisms isolated from the skin, but not demonstrated to be consistently present in the majority of persons. Such flora generally are considered to be transient but are of concern because it can readily be transmitted on hands unless removed by application of an antiseptic. Resident flora are organisms persistently isolated from the skin of most persons. These organisms are considered to be permanent residents of the skin and are not readily removed by mechanical friction or conventional antiseptics. The resident flora reside in sweat ducts, hair ducts, and within the stratum corneum up to more than 25 cell layers deep, however, the majority of the resident bacteria are found in the outer 0.3 mm of the skin.
After recognizing the need for more effective antiseptics, the United States Food and Drug Administration (FDA) developed performance standards for new and novel antiseptics which were published in the Federal Register 39:33103-33141 (Sep. 13, 1974). These performance standards required a surgical hand scrub to be broad spectrum, fast acting, and persistent, and a health care personnel hand wash to be broad spectrum, fast acting and, if possible, persistent. In the most recent rulings presented in the Federal Register 59:31402-31452 (Jun. 17, 1994), the same performance standards were upheld by the FDA, and testing procedures were given by which new antiseptics were to be comparatively tested against previously approved products.
The term broad spectrum is defined on Page 31422 of the Federal Register 59:31402-31452 (Jun. 17, 1994) as having antimicrobial activity against a variety of gram positive and gram negative bacteria, and yeasts.
A patient preoperative skin antiseptic preparation is required to be "a safe, fast-acting broad-spectrum antimicrobial-containing preparation which significantly reduces the number of microorganisms on intact skin." It is further defined as "effective against all types of organisms comprising skin microflora so as to obtain as low a number of microorganisms as possible in a short period of time without injury to the operative site." Federal Register 39:33114 (Sep. 13, 1974) Fast acting antiseptics are measured by significant log reduction determined by cultures obtained a few moments following application of the antiseptic.
The quality of persistence, or substantivity, refers to the ability of an antiseptic to continue to kill once it is applied. Substantivity is defined on Page 33110 of the Federal Register 39:33103-33141 (Sep. 13, 1974) as the retention or binding of the chemical in the stratum corneum of the skin after rinsing. According to the FDA, "a property [of an antiseptic] such as persistence, which acts to prevent the growth or establishment of transient microorganisms as part of the normal baseline or resident flora, would be an added benefit." Federal Register 59:31407 (Jun. 17, 1994). The degree of persistence is measured by the length of time required for the microflora to be fully restored to the baseline microbial count following the use of an antiseptic.
Currently there are several conventional antiseptics that are effective within twenty seconds against transient microorganisms which cause mammalian infection, e.g., 2% aqueous iodine, 70% ethanol, povidone-iodine, chlorhexidine acetate in 70% ethanol, and 2% tincture of iodine. This rapid antibacterial effect demonstrates their efficacy against the transient flora. However, rapid repopulation of bacteria from resident flora occurs with each of these antiseptic treatments. Thus, the FDA has approved use of antiseptics that are effective in reducing the number of transient organisms only on the surface of the skin but are less effective against resident flora within the stratum corneum.
Persistence has remained an elusive goal of antiseptic technology. Although persistence has been required by the FDA since 1974, it has only been achieved moderately with a single product, chlorhexidine gluconate. Only after repeated, daily applications, chlorhexidine has demonstrated antiseptic activity for about six hours. Larson, E., "APIC guidelines for infection control practice," Am J Infection Control 16:253-66 (1988). Thus, development of new and novel products that achieve far greater persistence with a single application than repeated applications of chlorhexidine gluconate would be a great improvement for infection control and would meet the standards that the FDA has promulgated since 1974.
As it is desirable to maintain medical procedures as free of microorganisms as possible, it is desirable to have persistence associated with an antiseptic that maintains the microorganism count at as low a level as possible and for as long as possible. This is especially true when an operation lasts for many hours. It is important to minimize the microorganism count of both the operative site and the hands of the surgeon for as long as possible. Persistence is also needed for antiseptics used around a chronic indwelling device such as central catheter, arterial line, or chest tube and for antiseptic treatment of hands of medical personnel in hospitals. Conventional antiseptics produce a rapid antimicrobial effect only on the transient flora and fail to exert a significant reduction of resident flora which may lead to infection with a very significant increase in morbidity and mortality. For example, in 1985, greater than $5-10 billion were spent to treat wound infections in American hospitals. (Wenzel, R. P., Am J Med 78(Supp 6B):3-7 (1985)). Consequently, there is a continuing need to improve antiseptics to provide simultaneous broad spectrum, fast acting activity, and persistent activity.
Novel antiseptics have now been found which are very broad spectrum, having antimicrobial activity against vegetative bacteria, yeasts, molds, and viruses, fast acting, and very persistent. Persistence is obtained with a single application. Cumulative persistence, greater than that achieved with alcoholic chlorhexidine gluconate, is obtained with daily use. These products are non-irritating and have reasonably pleasant characteristics associated with the senses of the persons using the antiseptic such as having a pleasant smell and a good tactile feel when applied to the skin. These antiseptics are easily modified to be used over a broad range of uses such as a topical antiseptic applied to the skin of humans or other mammals; a skin preparation antiseptic for use prior to medical operations or procedures; a hand wash for physicians and other medical personnel; a routine antiseptic handwash; an antiseptic at medical appliance invasive sites where needles, catheters, or tubes are placed within the skin or open wounds; a microorganism barrier or an antiseptic within various orifices such as the ear or vagina; an antiseptic to be utilized on sensitive membranes such as mucous membranes, eyes or genitalia; an antiseptic to be used in the treatment of inflammatory dermatoses, e.g., acne, athlete's foot, psoriasis and fungal infections; and an antiseptic treatment for use on animals to prevent infection, e.g., as a treatment against bovine mastitis.